Prescription Pattern of Tofacitinib for Alopecia Areata Among the Dermatologists in Saudi Arabia: A Cross-Sectional Study

Introduction Alopecia areata (AA) is a complex autoimmune condition that causes nonscarring hair loss. In Saudi Arabia, AA accounts for 1-2% of new dermatological outpatient visits. It typically presents with sharply demarcated round patches of hair loss and may present at any age. Traditional medical therapies include corticosteroids and immunotherapy. Choosing the ideal treatment depends on multiple factors such as patient age, disease severity, efficacy, side effects, and remission rate. Recent medications that have been used for treating AA are Janus kinase inhibitors. Aim The aim of the study is to assess the awareness and attitude of dermatologists and their use of Tofacitinib in treating AA. Method A cross-sectional study was conducted in 2019 across 14 major cities in Saudi Arabia. A self-administered online questionnaire was specifically developed and used. Dermatologists from government hospitals and private clinics were included through non-probability convenience sampling. The collected data was entered into Microsoft Excel and analyzed using SPSS program version 24. Results In total, out of 546 Dermatologists across Saudi Arabia who responded to the questionnaire, 127 (23.2%) physicians prescribed Tofacitinib in their practice. Out of those who prescribed the drug for AA cases, 58 dermatologists (45.6%) prescribed Tofacitinib after the failure of steroid injections. Among the 127 dermatologists who have utilized Tofacitinib in their practice, 92 (72.4%) believe that Tofacitinib is effective in treating AA. Almost 200 (47.7%) Dermatologists who never prescribed Tofacitinib reported that the main reason was due to the unavailability of the drug in the clinic they were practicing. Conclusions To conclude, out of 546 dermatologists working in Saudi Arabia, 127 (23.2%) prescribe Tofacitinib to treat AA. Ninety-two (72.4%) of the participants reported the effectiveness of Tofacitinib. Two hundred (47.7%) dermatologists who never prescribe Tofacitinib reported that the main reason was due to the unavailability. However, this would raise the need for more research regarding JAK inhibitors generally and Tofacitinib specifically, focusing on the effectiveness versus the side effects of Tofacitinib.


Introduction
Alopecia areata (AA) is a complex autoimmune condition that causes nonscarring hair [1]. In Saudi Arabia, AA accounts for 1-2% of new dermatological outpatient visits [2]. A systemic review indicated a similar worldwide lifetime incidence of around 2% [3]. It typically presents with sharply demarcated round patches of hair loss and may present at any age. AA has a variable clinical course with spontaneous remission, followed by exacerbations, or relentless progression to involve the entire scalp (alopecia totalis) and, uncommonly, all body hair (alopecia universalis; AU).
AA has an unpredictable prognosis and hair loss may spontaneously remit, although the timeframe for regrowth may be months to years [4]. There is a genetic predisposition to alopecia areata. About 20% of people with alopecia areata have a family history. The cause and mechanism of alopecia areata development are yet to be completely understood. However, genetic predisposition, immune system autoreactivity, and environmental precipitators are aspects that identify several processes and factors that have been proven to be major contributors to disease pathophysiology. AA is considered an autoimmune disease with a complex genetic component. Numerous gene mutations and polymorphisms have been identified to increase susceptibility to developing the disease; as well as other inflammatory and autoimmune diseases. Traditional medical therapies include corticosteroids, immunotherapy, and light therapy. Systemic medications such as corticosteroids, cyclosporine, and methotrexate have been used for severe forms but had many limitations including side effects and a high relapse rate. Recent medications that have been used for treating AA include Janus kinase inhibitors. These have been approved for treating other immunemediated & inflammatory diseases such as rheumatoid arthritis, myelofibrosis, and psoriatic arthritis by blocking the JAK inflammatory pathway that involves IL2, IL5, and IFN-γ. Oral and topical JAK inhibitor treatments have both prevented and reversed AA in mouse models. There have been several case series and reports demonstrating hair regrowth in patients with AA and AU. Moreover, many clinical trials are ongoing for AA involving JAK inhibitors such as ruxolitinib, tofacitinib, and baricitinib [5].
In this study, we seek to explore the awareness of dermatologists from multiple governmental and private hospitals in Saudi Arabia, aiming to assess their knowledge regarding the use and prescription of Tofacitinib for treating AA.

Materials And Methods
An observational cross-sectional study was conducted from October 2019 to March 2020 across 14 major cities in Saudi Arabia. The targeted areas are dermatology departments at both government hospitals and private clinics in Jeddah, Mecca, Al Taif, Abha, Jazan, Najran, Al Jouf, Tabuk, Hail, Al Dammam, Al Khobar, Al Ahsa, and Al Qatif. A self-administered online questionnaire was developed and collected using an electronic survey. The electronic survey was made using Google Forms software by the research team and distributed to all dermatologists. However, medical students and interns were excluded from the study. The questionnaire was validated through a pilot study on 25 doctors before distributing it. The total number of participants was 546 dermatologists. The collected data was entered into Microsoft Excel, exported, and then analyzed using SPSS program version 24. Categorical variables (e.g. gender) will be presented as percentages and frequencies. On the other hand, numerical variables (e.g. years of experience) will be presented by mean and standard deviation. The Chi-square test was used to compare categorical variables, and the ANOVA test was utilized for any numerical associations. A p-value of <0.05 indicated a statistically significant association.

Results
A total number of 546 responses were obtained from dermatologists practicing across the kingdom of Saudi Arabia (Riyadh, Jeddah, Dammam, Alahsa, Alkhobar, Alqatif, Makkah, Taif, Abha, Jazan, Najran, Aljouf, Ha'il, Tabuk). In total, dermatologists who used Tofacitinib for treating AA comprised 127 (23.3%) physicians, and 419 (76.7%) reported not having used Tofacitinib for treating AA ( Table 1), while only 11 (2%) dermatologists reported using a different type of JAK inhibitor (                The fact that dermatologists prescribed Tofacitinib in their practice was cross-matched with their characteristics. There was no statistically significant relation between prescribing Tofacitinib and the reported years of experience as consultants, with a p-value of 0.505. On the other hand, there was a statistically significant association between prescribing Tofacitinib and the gender of dermatologists, with a p-value of 0.000; that is, Tofacitinib was prescribed more by male dermatologists. A statistically significant relationship was found between prescribing Tofacitinib and the nationality (Saudi) of the dermatologist and their position title (residents), with both p-values of 0.000 (Table 16).  Results are based on nonempty rows and columns in each innermost subtable.
* The Chi-square statistic is significant at the .05 level.

Discussion
Tofacitinib is an oral JAK inhibitor that has shown promising results in treating alopecia areata as with other dermatological diseases [1][2][3][4]6]. The use of Tofacitinib and other JAK inhibitors for dermatological diseases, especially for AA, is relatively new and yet to be completely evaluated. Up to our knowledge, studies have not evaluated dermatologists' utility of Tofacitinib for AA. Therefore, this study aimed to provide insight into the prevalence of Tofacitinib use in treating AA and relevant related factors to its prescription among dermatologists in Saudi Arabia.
A retrospective study by Liu et al. in 2018 found that 90 patients with severe alopecia areata showed a significant increase in hair regrowth after 6 months of tofacitinib treatment [7]. In another study by Mackay-Wiggan et al. in 2016, 66% of their study population experienced 50% or greater hair regrowth after 3 months of tofacitinib treatment [8]. In another study, a systematic review and meta-analysis was done where multiple journals were chosen along with 1244 studies [9]. Of those 1244 studies, only 12 met their criteria where 346 patients that were diagnosed with alopecia areata were available. Of these 346 patients, 288 patients received oral Tofacitinib while 58 patients had oral Ruxolitinib as the treatment of choice [9]. They showed an overall achievement rate of 66% with the severity of the alopecia tool (SALT) [9]. While these studies show promising results of tofacitinib for alopecia areata, it is worth noting that tofacitinib may cause side effects such as increased risk of infection, gastrointestinal perforations, and changes in cholesterol levels. Further studies are needed to understand better the safety and efficacy of tofacitinib for treating alopecia areata. Nevertheless, dermatologists consider tofacitinib an off-label treatment option for patients with alopecia areata in cases where traditional treatments have failed to produce satisfactory results.
The majority (72.4%) of our respondents were dermatologists who have used Tofacitinib and believe the promising results in treating AA, as they reported agreeably regarding its efficacy in treating AA. However, when asked about their perception of its safety, 77.6% of dermatologists did not agree that Tofacitinib was safe. At the same time, there are studies that show a relatively safe profile of Tofacitinib [2][3][4]. In a study including rheumatoid arthritis patients, a long-term safety profile was documented for up to 9.5 years [3].
Only 23.2% of our respondent dermatologists utilized Tofacitinib in their practice. The main reported limiting factor of prescribing Tofacitinib was drug unavailability, as indicated by nearly half of the dermatologists (47.7%). Similarly, a study across Europe showed the underutilization of synthetic DMARDs, including JAK inhibitors, in treating rheumatoid arthritis was due to financial and administrative constraints [5]. Also, these limiting factors may lead to patterns of nonadherence among patients. In a study that assessed nonadherence to rheumatoid arthritis treatment, Tofacitinib and other biological DMARDs were found to have a primary nonadherence rate of 40.6% [10]. Factors that led to such high figures were sociodemographic variables like the insurance status of patients, age, and medical history [10].

Conclusions
To conclude, out of 546 dermatologists working in Saudi Arabia, 127 (23.2%) prescribe Tofacitinib to treat AA. Ninety-two (72.4%) of the participants reported the effectiveness of Tofacitinib. Two hundred (47.7%) dermatologists who never prescribe Tofacitinib reported that the main reason was due to the unavailability. However, this would raise the need for more research regarding JAK inhibitors generally, and Tofacitinib specifically, focusing on the effectiveness versus the side effects of Tofacitinib.